ALK+ NSCLC Landscape Shifting With Emerging Agents


“Ongoing clinical trials and a novel agent recently submitted to the FDA could expand the armamentarium for ALK-positive non–small cell lung cancer (NSCLC). Approved agents in the setting include the ALK inhibitors crizotinib (Xalkori), ceritinib (Zykadia), and alectinib (Alecensa).

“A new drug application (NDA) was submitted for brigatinib (AP26113) in August 2016 as a potential treatment for patients with ALK-positive disease. The NDA is partly based on encouraging results from the phase II ALTA study, which demonstrated a confirmed objective response rate of 54% for brigatinib at the 180 mg daily dose, including a 4% complete response rate.”

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FDA Submission Completed for Brigatinib in ALK-Positive NSCLC


“A new drug application (NDA) has been submitted for brigatinib (AP26113) as a potential treatment for patients with advanced ALK-positive non–small cell lung cancer (NSCLC) following resistance or intolerance to crizotinib (Xalkori), according the developer of the ALK inhibitor, Ariad Pharmaceuticals.

“The application was based on findings from the phase II ALTA study, which was presented at the 2016 ASCO Annual Meeting, along with results from an earlier phase I/II trial. In ALTA, the confirmed objective response rate (ORR) for brigatinib at 180 mg daily was 54%, which included a complete response rate of 4%. In those with measurable, active brain metastases treated with the 180 mg dose (n = 18), the intracranial ORR was 67%. Median progression-free survival (PFS) was 12.9 months.”

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Brigatinib Achieves Brain Metastases Control for Over 80% of ALK-Positive NSCLC Patients

“Brigatinib (AP26113), an investigational ALK tyrosine kinase inhibitor, demonstrated significant intracranial antitumor activity in patients with ALK-positive non–small cell lung cancer (NSCLC) and brain metastases, according to findings presented at the European Lung Cancer Conference.1

“A post hoc analysis conducted by Ariad Pharmaceuticals, the company developing brigatinib, looked at 49 NSCLC patients identified as having baseline brain metastasis. The analysis determined that intracranial disease control was achieved with brigatinib in 87% of patients with measurable brain metastases and in 87% of patients with nonmeasurable brain metastases. Intracranial response was reported in 53% of patients with measurable brain metastases and in 30% of patients with nonmeasurable lesions.

“Following treatment, 45 patients achieved median intracranial progression–free survival (PFS) of 22.3 months. The median duration of intracranial response was 18.9 months.

“Adverse events were mild to moderate in severity and included nausea, diarrhea, and fatigue that were reported by 29 (59%), 28 (57%), and 24 (49%) patients, respectively.”

The FDA Gives an Ariad Drug Candidate ‘Breakthrough Therapy Designation’

The gist: A new lung cancer treatment called AP26113 has shown promise for certain people with metastatic non-small cell lung cancer (NSCLC). Specifically, it is meant to treat people whose tumors have mutations in the ALK gene and who are resistant to the standard drug crizotinib. It has been tested in volunteer patients in clinical trials. The U.S. Food and Drug Administration (FDA) has now granted breakthrough therapy designation for AP26113, meaning that review and approval will be accelerated so that the drug can more quickly reach patients in the U.S., outside of clinical trials.

“Ariad Pharmaceuticals Inc. of Cambridge said Thursday that federal regulators have granted “breakthrough therapy designation” to a drug candidate for a form of lung cancer.

“According to the Food and Drug Administration’s website, a breakthrough therapy designation means that the FDA will expedite the development and review of such drug. The designation is given to drug candidates designed to treat a serious or life threatening disease that have shown great promise based on preliminary clinical evidence.

“Ariad’s drug candidate, currently dubbed AP26113, is for the treatment of patients with anaplastic lymphoma kinase positive metastatic non-small cell lung cancer who are resistant to crizotinib, an existing treatment on the market.

“Ariad’s press release cited data from the American Cancer Society. According to the society, non-small cell lung cancer is the most common form of lung cancer, accounting for about 85 percent of the estimated 228,190 new cases of lung cancer diagnosed each year in the United States.”

Identification of Mutations Causing Lung Cancer Resistance Leads to New Treatment Strategies

The gist: Two patients with lung cancer may have distinctly different tumors that make them respond differently to the same treatment. Oncologists can use molecular tests to determine which treatments might work for which patients. These molecular tests find genetic mutations in tumors. These mutations can be targeted with specific targeted drugs. However, tumors can develop new, additional mutations that make them resistant to targeted drugs. Recent research looked at mutations that cause resistance to a drug called alectinib. (Alectinib is meant to treat tumors with mutations in the ALK gene.) The researchers identified mutations that were causing the resistance, and identified two drugs, ceritinib and AP26113, that could be used as alternatives for patients resistant to alectinib. Indeed, one patient who was resistant to alectinib was successfully treated with ceritinib.

“Two mutations that cause lung cancer resistance to the investigational ALK inhibitor alectinib were identified, and this information may help design new treatment regimens for patients with ALK-positive lung cancer, according to a study published in Clinical Cancer Research, a journal of the American Association for Cancer Research.

“In 2014, more than 159,000 men and women are expected to die of lung cancer in the United States. About 84 percent of lung cancers are non-small cell lung cancers (NSCLC), and 3 to 5 percent of NSCLCs have mutations in the gene ALK.

” ‘The goal of our study was to determine why ALK-positive lung cancers become resistant to alectinib, and we looked at this in two different ways,’ said Alice T. Shaw, MD, PhD, a thoracic oncologist at the Massachusetts General Hospital Cancer Center. ‘We studied a resistant cell line model that we generated in the lab, and we also studied a tumor sample from a patient with NSCLC who had been treated with alectinib and then became resistant.

” ‘We discovered two novel mutations that have not been described before in patients with NSCLC, and these mutations conferred high-level resistance to alectinib,’ Shaw added. ‘Another equally important finding from this study is that we were able find a way to overcome this type of resistance, in our laboratory experiments as well as in a patient, using another next-generation ALK inhibitor, ceritinib, previously known as LDK378.’ “

ARIAD Presents Updated Phase 1/2 Data on AP26113 in Patients with ALK+ Non-Small Cell Lung Cancer

“ARIAD Pharmaceuticals, Inc. today announced updated clinical results on its investigational tyrosine kinase inhibitor (TKI), AP26113, in patients with advanced non-small cell lung cancer (NSCLC) from an ongoing Phase 1/2 trial. These study results show anti-tumor activity of AP26113 in patients with crizotinib-resistant anaplastic lymphoma kinase (ALK) positive NSCLC, including patients with brain metastases. Crizotinib is approved for ALK-positive NSCLC patients.”

Editor’s note: This story is about a targeted drug called AP26113, which may benefit some patients with advanced non-small cell lung cancer (NSCLC). Specifically, it has shown promise for patients whose tumors have mutations in the ALK gene, as detected by molecular testing, and who have already been treated with the drug crizotinib (Xalkori) but have grown resistant to it.

Thwarting Drug Resistance in Lung Cancer

If you’ve read up on lung cancer research in the last few years, you probably know that large strides have been made in targeted therapies for non-small cell lung cancer (NSCLC). Targeted therapies are drugs that identify and attack specific mutated proteins that are detected in tumors. Because noncancerous cells do not have these specific mutations, targeted therapies can make a beeline for cancer, while leaving healthy tissue unharmed. Continue reading…

New ALK Inhibitor Shrinks Lung Cancer in Early Trial

On the strength of promising results from an ongoing clinical trial, reseachers are starting a new trial for people with non-small cell lung cancer (NSCLC) that has abnormal ALK genes. This update was presented at the 2013 European Cancer Congress in Amsterdam, Netherlands. The phase I/II trial included 34 people with NSCLC with ALK abnormalities who were treated with an ALK inhibitor called AP26113. Tumors shrank in nearly all of the patients, including tumors that had spread to the brain, as well as those that resisted another ALK inhibitor called crizotinib (Xalkori). The new trial will test how well AP26113 shrinks NSCLCs that both have ALK abnormalities and are resistant to crizotinib.

Promising Early Trial Results for New Lung Cancer Drug AP26113

An ongoing phase I/II clinical trial of the cancer drug AP26113 has produced encouraging preliminary results. The study examines patients with advanced non-small cell lung cancer (NSCLC) who have not responded, or have become resistant, to other treatments. AP26113 shrank tumors in the majority of patients with mutations in the ALK gene, including several whose cancer had spread to the brain. Effects were seen both in patients who had never been treated with the ALK inhibitor crizotinib (Xalkori) and patients who had become resistant to Xalkori. Preliminary evidence also suggests that AP26113 may be effective in patients with mutations in the EGFR gene who have become resistant to EGFR inhibitors like erlotinib (Tarceva) and gefitinib (Iressa). AP26113, which inhibits both ALK and EGFR, was well tolerated and serious side effects were rare. The trial is moving ahead into phase II based on these findings.